Minimizing Toxicity in HLA-identical Sibling Donor Transplantation for Children With Sickle Cell Disease
NCT ID: NCT03587272
Last Updated: 2024-12-24
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE2
100 participants
INTERVENTIONAL
2018-04-17
2030-11-30
Brief Summary
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Detailed Description
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With protocol version 5.0, added new secondary objective to determine if the change from intravenous to subcutaneous alemtuzumab and the addition of post-HSCT G-CSF can decrease the incidence of poor donor engraftment.
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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SUN regimen
Alemtuzumab, low dose total body irradiation, Sirolimus
HLA-identical sibling donor transplantation using alemtuzumab, low dose total-body irradiation, and sirolimus (Sickle transplant Using a Nonmyeloablative approach, "SUN") can decrease the toxicity of transplant while achieving a high cure rate for children with sickle cell disease (SCD).
Alemtuzumab, low dose total body irradiation, Sirolimus
The conditioning regimen (SUN regimen) will consist of alemtuzumab daily for 5 days (total dose 1 mg/kg) and low dose total body irradiation (TBI) 300 cGY on Day -2 with gonadal shielding if possible. The HSCT graft will be G-CSF mobilized PBSCs with minimum CD34+ of 5 x106/kg recipient weight, goal of 10 x 106/kg (no upper limit). A peripheral blood stem cell (PBSC) graft was selected as it engrafts faster than bone marrow and would lead to shorter period of neutropenia and infection and less thrombocytopenia and need for platelet transfusion.
GVHD prophylaxis will be sirolimus with a loading dose 3 mg/m2 on day -1. Sirolimus will be continued at 1 mg/m2/day starting on day 0 and dose adjusted to maintain a target trough level 5-15 ng/mL for the first 3 months and 5-10 ng/mL for the remainder of the first year.
Interventions
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Alemtuzumab, low dose total body irradiation, Sirolimus
The conditioning regimen (SUN regimen) will consist of alemtuzumab daily for 5 days (total dose 1 mg/kg) and low dose total body irradiation (TBI) 300 cGY on Day -2 with gonadal shielding if possible. The HSCT graft will be G-CSF mobilized PBSCs with minimum CD34+ of 5 x106/kg recipient weight, goal of 10 x 106/kg (no upper limit). A peripheral blood stem cell (PBSC) graft was selected as it engrafts faster than bone marrow and would lead to shorter period of neutropenia and infection and less thrombocytopenia and need for platelet transfusion.
GVHD prophylaxis will be sirolimus with a loading dose 3 mg/m2 on day -1. Sirolimus will be continued at 1 mg/m2/day starting on day 0 and dose adjusted to maintain a target trough level 5-15 ng/mL for the first 3 months and 5-10 ng/mL for the remainder of the first year.
Eligibility Criteria
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Inclusion Criteria
* History of an abnormal transcranial Doppler measurement defined as TCD velocity ≥200 cm/sec by the non-imaging technique (or ≥185 cm/sec by the imaging technique) measured at a minimum of two separate occasions.
* History of cerebral infarction on brain MRI (overt stroke, or silent stroke if ≥3 mm in one dimension, visible in two planes on fluid-attenuated inversion recovery T2-weighted images).
* History of two or more episodes of acute chest syndrome (ACS) in lifetime.
* History of three or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in lifetime.
* History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment.
* History of two or more episodes of priapism (erection lasting ≥4 hours or requiring emergent medical care).
* Administration of regular RBC transfusions (≥8 transfusions in the previous 12 months).
* At least two episodes of splenic sequestration requiring red blood cell transfusion or splenectomy after at least one episode of splenic sequestration.
Patients with all other sickle genotypes (hemoglobin SC, Sβ+ thalassemia) must have at least one of the following:
* Clinically significant neurologic event (overt stroke).
* History of two or more episodes of ACS in the 2-years period preceding enrollment.
* History of three or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in the 1-year period preceding enrollment.
* History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment.
* History of two or more episodes of priapism (erection lasting ≥4 hours or requiring emergent medical care).
* Administration of regular RBC transfusions (≥8 transfusions in the previous 12 months).
* At least two episodes of splenic sequestration requiring red blood cell transfusion or splenectomy after at least one episode of splenic sequestration.
Exclusion Criteria
* Infection Disease: Uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms) within 1 month prior to conditioning. Patients with febrile illness or suspected minor infection should await clinical resolution prior to starting conditioning. Patients with confirmed seropositivity for HIV and patients with active Hepatitis B or C determined by serology and/or NAAT are excluded.
* Liver: Direct (conjugated) bilirubin \> 1.5 mg/dL, transaminases \>5x upper limit of normal for age.
* Cardiac: Left ventricular shortening fraction \<25% or ejection fraction \<50% by ECHO.
* Kidney: Estimated creatinine clearance less than 60 mL/min/1.73m2.
* Pulmonary function: Diffusion capacity of carbon monoxide (DLCO) \<35% (adjusted for hemoglobin). Baseline oxygen saturation \<85% or PaO2 \<70.
* Heme: History of RBC alloantibodies against donor RBC antigens (even if current antibody screen is negative). Major ABO incompatibility with donor.
2 Years
25 Years
ALL
No
Sponsors
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Alberta Children's Hospital
OTHER
The Hospital for Sick Children
OTHER
Levine Children's Hospital
OTHER
Ann & Robert H Lurie Children's Hospital of Chicago
OTHER
Nationwide Children's Hospital
OTHER
The Children's Hospital at Montefiore
OTHER
Columbia University
OTHER
Robert Nickel
OTHER
Responsible Party
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Robert Nickel
Principal Investigator
Principal Investigators
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Robert Nickel, MD
Role: PRINCIPAL_INVESTIGATOR
Children's National Research Institute
Locations
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Children's National Health System
Washington D.C., District of Columbia, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States
Columbia University
New York, New York, United States
Levine Children's Hospital
Charlotte, North Carolina, United States
Nationwide Children's Hospital
Columbus, Ohio, United States
Alberta Children's Hospital
Calgary, Alberta, Canada
The Hospital for Sick Children
Toronto, Ontario, Canada
Countries
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Central Contacts
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Facility Contacts
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Maryanne Odinakachukwu
Role: primary
Fahmida Hoq, MBBS, MS
Role: backup
Olga Jonas
Role: primary
Ella Ramsey
Role: backup
Jaclyn Dosik
Role: primary
Janice Hollifield
Role: primary
Hemalatha Rangarajan
Role: primary
Gregory Guilcher
Role: primary
Role: backup
Umer Muzzamil
Role: primary
Brandon Rothberg
Role: backup
References
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Leonard A, Furstenau D, Abraham A, Darbari DS, Nickel RS, Limerick E, Fitzhugh C, Hsieh M, Tisdale JF. Reduction in vaso-occlusive events following stem cell transplantation in patients with sickle cell disease. Blood Adv. 2023 Jan 24;7(2):227-234. doi: 10.1182/bloodadvances.2022008137.
Other Identifiers
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IRB 10322
Identifier Type: -
Identifier Source: org_study_id